Datasets:

etanios

/

shortened-pubmed

like 0

An effect of diuretics on cellular metabolism has been shown. In order to examine further the direct effect of diuretics on renal mitochondria, their effect on isolated cortical (C) and outer medullary (OM) mitochondrial respiration was examined. Oxygen consumption rate (QO2) was measured in a Gilson oxygraph utilizing either glutamate-malate or succinate as substrate. QO2, expressed in nanoatoms of O2 per milligram of protein per minute, was always higher in C than OM: 140.7 +/- 2.8 VS. 121.2 +/- 2.4 (P less than 0.001) with glutamate-malate and 181.1 +/- 6.3 vs. 129.7 +/- 5.2 (P less than 0.001) with succinate. A dose-response curve was constructed for each of the following: sodium ethacrynate, furosemide, chlorothiazide, acetazolamide and chlormerodrin. All diuretics inhibited C and OM equally. The 50% inhibitory molar concentration for EA was 6.2 times 10(-4); for furosemide 1.5 times 10(-3); for chlorothiazide 8.1 times 10(-3); for acetazolamide 10.8 times 10(-3); and for chlomerodrin 3.1 times 10(-5). Neither cysteine nor dithiothreitol inhibited the effect of EA. The effect of chlormerodrin was abolished by cysteine. These results demonstrate that while a difference exists between C and OM mitochondria during control studies, each of the diuretics examined exerted an equal inhibitory effect on mitochondrial respiration from both C and OM. Mercurials are the most potent inhibitors and presumably exert their effect by reacting with sulfhydryl groups. They are followed in potency by ethacrynic acid, furosemide, chlorothiazide and acetazolamide.

A derivative of imidazole, 1-benzylimidazole [(1-phenylmethyl)-H-imidazole], was found to have strong cardiotonic activity. In isolated ventricular strips of rabbits, 6.3 times 10(-5) M 1-benzylimidazole (BI) increased contractile force by 100%, and in the intact cat, 0.5 mg/kg of BI increased cardiac output by 30 to 40%. The increase was maintained in both preparations for 5 to 30 minutes. Heart rate was not changed in the atropine-pretreated cat. Basic cycle length, recorded intracellularly in rabbit sinoatrial nodal cells, was increased by 8%. Since BI had many actions similar to the cardiac glycosides, including the absence of effects on rate and resistance to adrenergic beta blockers, it was of interest to determine whether BI and ouabain could interact and modify, or enhance their respective actions. In combination, it was found that ouabain and BI had summative effects on contractility and maintained the frequency-force relationships. In this respect, the action of BI is similar to that of glucagon and Ca++, but not to that of the catecholamines.

Varying concentrations of ethyl alcohol were injected either into the left main coronary artery or intravenously in anesthetized intact dogs. Effects of alcohol on intracardiac conduction (by His bundle electrogram) were examined at spontaneous and paced (atrial) heart rates. Alcohol by the intracoronary route prolonged atrioventricular node and intraventricular conduction times by approximately 5 to 15%. These changes preceded a depression of left ventricular systolic pressure and of the rate of rise of left ventricular pressure and an elevation of left ventricular end-diastolic pressure. Intracoronary injections of contrast medium (sodium diatriozoate) or iso-osmolar solutions of sucrose and injections of similar amounts of alcohol in the ascending or descending aorta did not affect intracardiac conduction. Increasing atrial pacing rates resulted in prolongation of atrioventricular nodal conduction intervals, but did not influence intraventricular conduction time. At each pacing rate, alcohol depressed both atrioventricular nodal and intraventricular conduction. The data suggest that alcohol has a direct depressant effect on intracardiac conduction.

It was hypothesized that self-actualization (SA) assessed by scores on the Personal Orientation Inventory should affect the salience of interpersonal stimuli and moderate the attitude similarity/dissimilarity relationship. Fifty-six American college students (28 males and 28 females), aged 18-21, were used as subjects. In Experiment I SA and proportion of attitude similarity were varied by use of Byrne's attraction paradigm in a between-Ss design. The personality variable failed to affect attraction. In Experiment II SA and proportion of attitude similarity were manipulated in a within-Ss design. SA Ss rated the stranger significantly higher in attraction at high levels of similarity and significantly lower in attraction at low levels of similarity when compared to non-SA individual (p smaller than .05). The results were discussed in terms of design differences in personality research and the potential mechanism (self-esteem) by which SA affects attraction.

This study investigated the relationship between behavioral adjustment of mental hospital patients and helping behavior in two distinctly different controlled situations. Forty hospitalized male patients between the ages of 20 and 45 were assigned to two groups of equal size according to ratings they received on the MACC Behavioral Adjustment Scale. Each subject was exposed to two separate and independent experimental situations calling for helping behavior. Helping in the first situation was defined as offering a confederate the use of an extra pencil, while in the second it was defined as offering to help a confederate in the hallway to pick up a box of pencils that had just been dropped. The results of both experiments confirmed the hypothesis that persons suffering more severe levels of disturbance and maladjustment perform significantly fewer helpful acts. Results were discussed in terms of empathy, self-concern, and response cost. Also some implications for treatment were discussed.

The ultrastructural changes in the cytoplasm of lethal hybrids obtained by nuclear transplantation between different strains of Amoeba proteus were compared with those of enucleated amebae. It was found that, whereas the Golgi complex and glycocalyx degenerated first in enucleated cells, mitochondria and endosymbiotes became abnormal first in the hybrids. The selective effects are attributed to the presence of nucleic acids in the mitochondria and endosymbiotes and hence to the different interactions they would have with the nuclear genome.

The language behavior of field-independent (F-D) clinically normal, verbally resourceful femal college students was examined in three different communication conditions: Dialogue, Warm (vissually supportive) monologue, and Cold (visually nonsupportive and stressful) Monologue. F-I and F-D Ss produced similar amounts of the different types of language behavior evaluated in each of the three communicative conditions. However, they differed with respect to verbal output and length of sentence "packaging" unit in Monologue conditions. F-D Ss talked considerably less but at the same time produced different types of grammatically more elaborate language behavior in Warm and Cold Monologue compared to their Dialogue language behavior. F-I Ss talked considerably more but also showed a type of language autonomy. The pattern of language behavior which characterized F-I speech in Dialogue remained the same in both Monologue conditions.

Slow progress in the first stage of labour was treated in 792 mothers by digital dilatation. This manoeuvre is described. Partial dilatation was converted to complete dilatation in 94.4 per cent of all cases, the incidence of success being 90.0 per cent in primiparae and 96.0 per cent in multiparae. Difficulties are described, but serious complications were conspicuously absent.The manoeuvre was helpful with mothers unable to resist premature bearing down, and especially valuable for reducing delay before applying forceps for fetal distress. The early perinatal loss of 20 (in the first 200 cases) was reduced to 3.3 (in the last 599 births) after a change of technique.

Recurrent injuries in children should be regarded as a symptom complex rather than a diagnosis of ;accident proneness'. Investigation, which may include much listening will often reveal a family with emotional problems. The family doctor who can see the family as a whole is often best placed to offer or co-ordinate help.

Recent trends in general practice towards working in multi-disciplinary teams from purpose-built premises have emphasised the need to study the ways in which doctors and other staff spend their working time.This paper describes a well-established work-study technique (activity sampling), which has been adapted to enable doctors to assess how they use their time. The method needs no observer and is cheap to operate. Five general practitioners undertook to record their surgeries for two separate weeks using the bleep method of activity sampling. The results they obtained show that the technique is both practicable in normal working conditions and is capable of providing information highly relevant to the management of general practice.

The report of the Joint Working Party on General Medical Services (1973) considered in detail the provision of electrocardiographic services for general practitioners. These are based either on primary health care teams using their own apparatus, or on hospitals offering open-access to their cardiac departments.In this survey I attempted to compare the proportions of general practitioners using their own electrocardiographs with those using hospital-based apparatus, and with those without direct access to any electrocardiograph facilities, and to evaluate the use made of such services, when available.

In a group of 64 patients (29 men and 35 women) all aged 65 or over referred for electrocardiography in this Department, there were 30 (16 men and 14 women) with no recorded clinical evidence of major cardiovascular disorders, past or present. Of these ;clinically negative' patients 19 (ten men and nine women) showed codable abnormalities when their electrocardiograms were read and classified according to the Minnesota code.In a group of 121 patients (63 men and 58 women) aged 42-64 only seven (six men and one woman of 58) ;clinically negative' patients showed codable abnormalities in their electrocardigrams. It is suggested that the high yield of codable abnormalities in the former group reflects incomplete and misleading cardiovascular histories or atypical clinical presentations in that group and a plea is made for a more widespread use of routine electrocardiography when trying to sort out the often multiple and confusing clinical problems of the elderly.

Selected samples of healthy people (804 males, 796 non-pregnant females and 400 pregnant women) were questioned about present and previous urinary symptoms. Mid-stream specimens of urine were cultured quantitatively. Symptoms in the males occurred more frequently in the presence of ;significant bacteriuria', but the numbers were too small to allow statistical analysis. Among the non-pregnant females frequency or burning micturition was found more frequently in those who had significant bacteriuria than in those whose urinary bacterial counts were low; for nocturia this difference was statistically significant (p <0.001).Of the pregnant women, comparison of those who had significant bacteriuria with those whose urine was normal showed that diurnal and nocturnal frequency, and loin pain, occurred more frequently in those with significant bacteriuria (for each of these symptoms p <0.0.1).These results suggest that the recent onset of nocturia is the most reliable symptom of urinary tract infection. There remain, however, many people with urinary symptoms and with low urinary bacterial counts in whom other causes for the symptoms should be sought.

Pregnant hamsters were ovariectomized on Day 7 and daily supplements of progesterone or progesterone plus oestradiol benzoate were given. Fetal development and survival was 14% and 62% respectively. Histological examination indicated that failure of labyrinthine development in the placenta resulted in failure to form an adequate number of maternal arterial spaces communicating with the base of the trophospongium to allow trophoblast migration in the related maternal spiral arteries. Progesterone was essential at all stages of gestation to sustain decidualized tissues and allow survival of a minority of fetuses. Oestradiol supplementation significantly increased fetal survival, but not to normal levels, suggesting that other oestrogens may be essential for the maintenance of normal hamster pregnancy.

Intravaginal administration of 5HT was effective in terminating pregnancy when given after implantation in the rat, provided that the tampon was allowed to remain in the vagina for 4 hr or more. Complete antifertility efficacy was associated with a prevention or reversal of the increase in ovarian weight, which occurs in untreated rats between Days 12 and 17 of pregnancy, and correlates with enlargement of the CL. Data from hysterectomized, ovariectomized and progesterone-implanted rats indicated that the effect on CL was not a cause of the antifertility effect. Intravaginal administration of 5HT was found to lead to general systemic effects.

The Franklin and Dukes (FD) test is used as a screening test for the determination of sperm-agglutinating antibodies and as a proof of therapeutic effects in cases of infertility, but various parameters of the FD test remain unclear and the application of different techniques has revealed highly different results. To test the statistical evidence for the FD technique, conditions regarded as optimal prerequisites were applied: a sperm concentration of 20 times 10(6)/ml was produced with Baker's buffer and serum dilutions were made with Baker's buffer, starting at 1:4. Only the standard deviation of parallel tests with one serum sample and one semen sample on the same day was found to be within an acceptable range. Using ejaculates of the same donor and the same serum sample on different days gave results that were not reproducible. The FD test should not, therefore, be used for quantification of sperm-agglutination antibodies except for a comparison in one test with one semen sample on the same day. Although the FD test only allowed a qualitative evaluation of sperm-agglutinating antibodies the % sperm agglutination was more informative than agglutination titres. For quantification of sperm-agglutinating antibodies, the FD test should be replaced by other techniques.

Endometrium was obtained from cattle slaughtered at various stages of early pregnancy and of the oestrous cycle. Analyses for protein, RNA, DNA, glucose and some lysosomal enzymes were carried out on this tissue. The results are considered with respect to the general influence of the hormonal status of pregnancy and the specific influence of the hormonal status of pregnancy and the specific influence of the blastocyst in one uterine horn.

Ovarian cycles and the pattern of reproduction in female black-tailed deer in British Columbia were ascertained largely through examination of the ovaries from 444 females. Cyclic development and degeneration of single follicles of ovulatory size occurred several weeks before first ovulation. As the breeding season approached, a second or third large follicle developed in each cycle but in 48% of adult females the follicles were at different stages of maturation. Those failing to rupture at first ovulation luteinized 1 to 2 days thereafter. The first ovulation of the season, in November, never resulted in a lasting pregnancy even though some ova were penetrated by spermatozoa and began to cleave. First ovulation was apparently 'silent' in five of seven females for their ova lacked spermatozoa. Of sixty-one pregnant females, fifty-nine conceived at second ovulation; the other two conceived at subsequent ovulations more widely spaced than the 8- to 9-day interval between first and second ovulations. The synchrony of ovulatory cycles among adult females was such that half of them ovulated for the second time in a span of 7 or 8 days. Primary CL that formed after first ovulation grew to an average maximum volume of only about 45 mm3, whereas those originating at second ovulation grew to twice that size within 5 to 8 days. First generation CL shrank from 35 mm3 to 10 mm3 within 2 days. They disappeared within 18 months but corpora albicantia persisted for the life of the female. The possible ecological significance of the reproductive pattern is discussed.

The isoelectric points of washed spermatozoa from intact boars and from boars after removal of the seminal vesicles were determined using isoelectric focusing on natural pH gradients. Normal boar spermatozoa focused at a higher pH than spermatozoa from boars without seminal vesicles. The isoelectric point of the latter was increased to a value approaching normal by preincubation in normal seminal plasma. This indicates that seminal plasma alters the membrane surface charge of boar spermatozoa on ejaculation.

For the synthesis of [1-L-penicillamine,4-L-leucine]oxytocin (2), Z-Tyr(Bzl)-Ile-Leu-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2 was treated with anhydrous HBr, and the resulting partially deprotected octapeptide was coupled with Z-penicillamine(Bzl) in a condensation reaction mediated by dicyclohexylcarbodiimide and 1-hydroxybenzotriazole. The protected nonapeptide Z-penicillamine(Bzl)-Tyr-Ile-Leu-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2 was treated with Na in NH3 and the resulting disulfhydryl compound was subjected to oxidative cyclization in H2O-CH3OH with ICH2CH2I, Purification of 2 was effected by partition chromatography and gel filtration. The analog possesses antioxytocic and antiavian vasodepressor pA2 values of 6.77 and 7.21, respectively, and has no antipressor or anti-ADH activity. Its biological activity spectrum is qualitatively identical with that of [1-penicillamine]oxytocin. In contrast to the marked natriuretic-diuretic and anti-antidiuretic activity of [Leu4]oxytocin, 2 exhibits none of these effects on the rat kidney.

[4-Phenylalanine]oxytocin was prepared from Z-Cys(Bzl)-Tyr(Bzl)-Ile-Phe-Asn-Cys(Bzl)-Pro-Leu-Gly-NG2 (4) by deprotection with Na in NH3 followed by cyclization of the resulting disulfhydryl compound with ICH2CH2I. The protected peptide 4 was prepared from Boc-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2 by the stepwise solution method. Coupling was effected by a modification of the dicyclohexylcarbodiimide-1-hydroxybenzotriazole preactivation method wherein the precipitate of dicyclohexylurea is removed by filtration prior to mixing of the amino and carboxyl components. The analog was found to be an effective inhibitor of the antidiuretic (ADH) response to exogenous arginine-vasopressin. It produced marked diuresis in the anti-ADH assay at approximately the same dose level as does [Leu4]oxytocin but, in contrast to [Leu4]oxytocin, showed natriuretic activity only at relatively high dose levels. In addition, [Phe4]oxytocin exhibited 0.15% of the oxytocic potency of oxytocin, weak antiavian vasodepressor activity (pA2 = 6.93), and no measurable rat pressor activity.

A series of 19 aliphatic analogs of 2,8-dibenzylcyclooctanone and 1,5-diphenyl-2,4-dimethyl-3-pentanone was examined. Separation of hypocholesterolemic activity from the previously observed uterotropic and antifertility activities was achieved by simplification of the parent compound to 2-octanone. There was no loss of hypocholesterolemic activity. Reduction of serum cholesterol levels in male rats to less than 50% of control values was obtained at a dose of 10 mg/kg/day.

The (+/-) title compound was prepared to evaluate prior observations that certain acetylcholine congeners derived from cyclobutane are devoid of muscarinic effects. It was prepared by a multistep sequence from trans-2-carbomethoxycyclobutyl methyl ketone. In a guinea pig ileum assay, it was 0.02 times as active as AcCh, and in a dog blood pressure assay, it was 0.09 times as active. In these assays, its (+/-)-cyclopropane congener and AcCh were equally active. This is the first cyclobutane-derived AcCh congener possessing significant muscarinic effect.

A method is described for the preparation of 13N-labeled N-nitrosoureas, specifically 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. The 13N is generated as ammonia by the 12C(d,n)13N reaction on methane gas. The product is selectively trapped and subsequently oxidized to nitrous acid which reacts with the parent urea in solution to form the 13N-labeled nitrosourea.

The elucidation of the structure of a new major metabolic product of hydralazine, 3-hydroxymethyl-s-triazolo[3,4-a]-phthalazine, is described. The structures of several other previously described metabolites of the drug, phthalazone, s-triazolo[3,4-a]phthalazine, and 3-methyl-s-triazolo[3,4-a]phthalazine, are confirmed. A metabolic pathway of hydralazine is also proposed.

3,6-Diacetylnormorphine (norheroin) and 6-acetylnormorphine have been prepared in excellent yield through the 3,N-bis(tert-butoxycarbonyl) derivative of normorphine via acetylation and selective removal of protecting groups. This general procedure would be applicable to the preparation of various 3,6-diesters or 6-monoesters of normorphine. The analgesic potency of norheroin was found to be the same as that of 6-acetylnormorphine, about 0.05 that of heroin. The onset, peak, and duration of action of these compounds were nearly identical and comparable with morphine.

A homologous series of 3-alkyl-1,2,3,4,5,6-hexahydro-8-hydroxy-6-methyl-3-benzazocines (2) has been synthesized. Analgetic activity and binding constants for the opiate receptor for 2 and for an analogous series of benzomorphans (1 and 3) are reported. In 1, hot-plate analgesic activity is lost on increase of the N-alkyl chain length from ethyl through butyl (lc-e) and regained with amyl (lf) and hexyl (lg). Compounds lc-e show that antagonist properties and binding constants are similar throughout the series. With 2, where there has been loss of steric constraints through removal of the 2,6-methano bridge of 1 and 3, greatly diminished analgetic activity and receptor affinity and no antagonist properties were observed. Like 1, however, greatest agonist activity was shown by the N-methyl (2c), amyl (2g), hexyl (2h), and heptyl (2i) homologs and there is a parallel of in vitro binding strength and analgetic activity.

Preparation of both a 5'-deuterium and a 5'-tritium-labeled 9-beta-D-arabinofuranosyladenine (6a and 6b) by reduction of the protected 5'-aldehyde 4 is described. Conversion of 6b to the 5'-tritium-labeled 5'-monophosphate 7b was effected directly with a phosphoryl chloride-formic acid reagent. The product 7b exhibited consistently higher blood levels of nonvolatile tritium than the 2-labeled compound when tested in dogs.

[1-Beta-Mercaptopropionic acid,2-(3,5-dibromo-L-tyrosine)]oxytocin was synthesized from a protected polypeptide intermediate that had been prepared by the condensation of S-ethylcarbamoyl-beta-mercaptopropionyl-3,5-dibromotyrosine with H-Ile-Gln-Asn-Cys(Ec)-Pro-Leu-Gly-NH2, using dicyclohexylcarbodiimide in dimethylformamide. The ethylcarbamoyl (Ec) protecting groups were removed by refluxing NH3, and the resulting disulfhydryl peptide was oxidatively cyclized to the corresponding disulfide by ICH2CH2I. Purification of the analog was effected by partition chromatography and gel filtration. The analog possesses antioxytocic (pA2 = 7.05) and antiavian vasodepressor (pA2 = 7.44) activities but has neither agonist nor antagonist activity in the rat pressor assay.

The Fibonacci search technique, first applied to a structure-activity study by Bustard, has been expanded to allow the analysis of a broad class of structural types of compounds. The compounds are first arranged in order of increasing value of a molecular property of the analogs such as log P, Sigmapi, Sigmasigma, or Rm. A successful Fibonacci search of the compounds will find the most active analog in a small, predetermined number of steps. Examples are given where insight as to mechanism of action is indicated by the combination of various parameters such as log P and pKa. Additional examples illustrate the use of Fibonacci search to establish the parabolic dependence of the biological activity of lipophilicity and sigma, where such dependency had not been observed initially. This technique allows the treatment of a variety of structurally diverse types of compounds simultaneously. It is to be stressed that Fibonacci search can be applied to structure-activity studies without the use of a computer.

The problem of structure-activity relationships in sulfonamide type compounds is tackled on the ground that both bacteriostatic activities and structural indices must be referred to the specific individual forms assumed by sulfa drugs in the active solutions. The frequency value of the symmetric stretching mode of the sulfonyl group upsilons (SO2) is chosen as a suitable electronic index and measured for the individual active forms in aqueous and Me2SO solutions. The linear correlation that exists between bacteriostatic parameter and vibration frequency (over the complete range of data at present available) proves a strict relationship between electronic structure and bacteriostatic activity in this class of drugs. Furthermore, it justifies the assumption used for the calculation of the bacteriostatic activity of the anionic form; i.e., in equilibrium with a very active species (the anion) a less active species (the neutral form) gives a negligible contribution or does not contribute at all to the total activity. The results can be summarized as follows: the lower the frequency of the symmetric stretching mode of the SO2 group of any active species of sulfonamide type compounds, the higher its bacteriostatic activity. The existence of a clear structure-activity correlation demonstrates that the whole class of compounds, whatever their form, has a single mechanism of action, while incontrovertible deviations from the general trend indicate differences or complications in the mechanism itself, but does not demonstrate that the group on which the structural index is localized plays a dominant role in the biological process. The usefulness of pKa and NH2 proton chemical shift of precursor amine as indirect indices of the electronic structure of the anionic forms is explored on extensive sets of available data.

The passage of nucleosides across the plasma membrane of erythrocytes is a membrane-mediated process which is strongly inhibited by derivatives of 9-beta-D-ribofuranosylpurine (1) with S, O, or N atoms at the purine 6 position bearing variously substituted arylalkyl groups. In this structure-activity study, nucleoside derivatives were compared in respect to their ability to inhibit a transport-dependent aspect of nucleoside metabolism in erythrocytes, the synthesis of inosine from external guanosine and hypoxanthine. 6-Benzylthio, 6-benzylamino, and 6-benzyloxy derivatives of 1 were inhibitory at 10(-5)-10(-6) M and the similarity of their activities suggested that alkylation of the transporter as the mechanism of transport inhibition was unlikely. The hydrophobicity of the 6-position substituents appeared to contribute importantly to inhibitory activity. Although replacement of the ribofuranose moiety by other sugars reduced inhibitory activity, compounds with 9-butyl groups were inhibitory. 6-[(2-Hydroxy-5-nitrobenzyl)thio] derivatives of 1 were the most potent of the inhibitors tested, being active at about 10(-7) M.

A series of 4-alkyl-8,9-dihydro[1]benzazepino[3,2,1-jk][1,4]benzodiazepin-1(2H)-ones and brominated derivatives was synthesized. Two approaches for the synthesis of 4-alkyl[1]benzazepino[3,2,1-jk][1,4]benzodiazepin-1(2H)-ones and brominated derivatives are described. All compounds were evaluated for CNS activity. None showed significant activity. The results obtained indicate that in the case of the 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one a phenyl group at the 1 position causes a fall in CNS activity not only when it is free but also when fused to the benzodiazepine system.

The synthesis and antilipidemic activity of 9-chloro-2,3-dihydro-5H-1,4-dioxepino[6,5-b]benzofuran (3), a novel enol lactone which is considerably more resistant to serum esterase hydrolysis than clofibrate (1), are discussed. Whereas both 3 and 1 reduced hypercholesterolemic and hypertriglyceridemic serum levels in the Triton WR-1339 induced hyperlipidemic Sprague-Dawley rat to normal, the hydrolysis product of 3, namely 5-chloro-3(2'-hydroxyethoxy)-2-benzofurancarboxylic acid (4), was found to be inactive. Further, 3 is comparable to the hydrolysis product of 1 when both were assessed for their ability to block norepinephrine (NE) induced lipolysis in vitro. 4 is inactive at comparable concentrations (5 times 10(-4)-10(-3) M). The antilipidemic action of 3 and 1 may, in part, be due to their ability to block NE-induced lipolysis.

The eight optically active stereoisomers and the corresponding four racemic forms of 5,9-dimethyl-2'-hydroxy-2-tetrahydrofurfuryl-6,7-benzomorphan (1) have been prepared. Depending on their configurations these compounds are potent analgesics or inactive substances in mice. The analgesics attain potencies up to about a hundred times that of morphine but they do not show morphine-like side effects in mice nor do they suppress abstinence in withdrawn morphine dependent monkeys. Their therapeutic ratios are favorable and, in the case of la-1 and la-2, exceptionally good. Configuration-activity relationships are discussed. R configuration of the N-tetrahydrofurfuryl group is a major prerequisite for high analgesic potency.

Microbial transformations of 10,11-dimethoxyaporphine were studied to determine the potential of microorganisms to produce monomethoxyaporphines. Ten microorganisms were identified as being capable of yielding apocodeine and/or isoapocodeine as the major metabolite in 24 and 20% yield, respectively. Cunninghamella blakesleeana (ATCC 9245) converted 10,11-dimethoxyaporphine quantitatively into isapocodeine. O-Dealkylation of this aporphine system is a facile microbial transformation, and the 10-methoxyl group is more susceptible to metabolic cleavage than the sterically hindered 11-methoxyl group. Selectivity in O-dealkylation may be accomplished with different microorganisms. This is the first report dealing with the microbial transformation of an aporphine system.

The trisulfide disulfinate [Na32S(CH2)4S]2S (2) is an antiradiation drug which is atypical in having no nitrogen function. At low dose levels of 37.5 and 18.5 mg/kg intraperitoneally (ip), 2 protected respectively about 82 and 35% of lethally irradiated mice. By the oral route (po), 150 mg/kg of 2 protected about 73%, and 75 mg/kg protected about 20%. The LD50 either ip or po exceeded 900 mg/kg. Although a 2,3-diacetoxy analog 3 was inactive, cyclic disulfide and trisulfide sulfinate analogs showed promice. Among these, a sulfinate moiety is related to a di- or trisulfie moiety in the sense of 1,8 in a naphthyl system (4,5), 2,2' in a biphenyl system (6-9), and alpha,alpha' in an o-xylyl system (10,11). The 1,8-naphthyl disulfide sulfinate 4 was not tested biologically because a marked neighboring group effect of -SO2Na on -SS- caused rapid cyclization to the parent disulfide dioxide 14; the corresponding trisulfide 5 was more stable but only slightly protective. Other analogs lacking the coplanarity of 4 also were more stable. The biphenyl compounds 6 and 7 were quite active ip (e.g., 7 led to 90% survival at 4.6 mg/kg, with LD50 EQUALS 130 mg/kg, although protection with 6 and 7 at the doses given po was only fair). Dichloro counterparts 8 and 9 offered no advantages over 6 and 7. The xylylene compounds 10 and 11 were roughly comparable to each other by ip and op routes (e.g., given ip, 10 led to 93-100% survival at 75 mg/kg, with LD50 GREATER THAN 950 mg/kg; given po, 10 gave 100% survival at 60 mg/kg, with LD50 GREATER THAN 900 mg/kg). Compounds 7 and 11 join 2 as promising antiradiation drugs that lack the usual nitrogen function. The fact that sulfinate salts show activity, both ip and po, suggests that the -SO2Na moiety deserves more attention in medicinal chemistry. Hydration of sulfinate salts often made analytical characterization difficult. Confirmatory evidence for typical structures is given.

The high antiradiation activity and low toxicity of sodium 3-amino-2-hydroxypropyl hydrogen phosphorothioate (1) suggested the introduction of hydroxyl groups into other types of radioprotective phosphorothioates. A number of such compounds were synthesized, including S-3-(3-aminopropylamino)-2-hydroxypropyl dihydrogen phosphorothioate (11, n equals 3), S-2-(3-amino-2-hydroxypropylamino)ethyl dihydrogen phosphorothioate (20) and its propyl homolog 26, N,N'-(2-hydroxytrimethylene)bis(S-2-aminoethyl dihydrogen phosphorothioate) (40), S-2-[3-(2-hydroxyethylamino)propylaminoi1ethyl dihydrogen phosphorothioate (44), and sodium S-2-amino-2-(hydroxymethyl)-3-hydroxypropyl hydrogen phosphorothioate (49). Compounds 11 (n equals 3), 20, 26, and 49 were highly protective when administered intraperitoneally but were generally ineffective when given perorally, as were the other hydroxylated phosphorothioates prepared. The introduction of hydroxyl groups significantly enhanced the radioprotective properties of nonhydroxylated parent compounds, however, only in the case of intraperitoneally administered.

Several novel steroidal alpha-methylene-gamma-lactones and related derivatives have been synthesized as potential steroid alkylating antitumor agents. The synthesis of these compounds involved the convenient Reformatsky-type reaction between ethyl-alpha-(bromomethyl)acrylate and the proper steroidal ketones. In vitro assay for the cytotoxicity of these compounds against the growth of tissue culture cells originating from human epidermoid carcinoma of the larynx (H.Ep.-2) has shown significant activity. Cytotoxicity was improved at least sixfold with the introduction of lipophilic steroidal character. Preliminary in vivo tumor assay also indicated that these compounds were active against Walker 256 carcinosarcoma in rats and were inactive against both L1210 lymphoid leukemia and Ehrlich ascites carcinoma in mice. However, the simple alpha-methylene-beta,beta-dicarbethoxy-gamma-butyrolactone significantly inhibited Ehrlich ascites tumor growth.

A variety of esters of 17-hydroxy-3-oxo-17alpha-pregn-4-ene-7alpha,21-dicarboxylic acid-gamma-lactone (7a) was synthetized in a sequence using the corresponding 3-oxo-4,6-diene (2) as starting material. The methyl (5), ethyl (7c), and isopropyl (7e) esters as well as the C-1 unsaturated methyl ester (8a) showed good oral and subcutaneous activity (MED less than or equal to 0.41 mg). Some general observations on structure-activity relationships are made.

Some glycine, leucine and phenylalanine dipeptide derivatives of the transport inhibitory, tricycloaliphatic alpha-amino acid, adamantanine (1), have been synthesized using classical methods of peptide synthesis with the aim of improving the latter's bioavailability. Although test doses of glycyladamantanine and L-leucyladamantanine appeared to be absorbed in vivo as evidenced by its appearance in the uring following intraperitoneal administration, they were not hydrolyzed by a purified preparation of leucine aminopeptidase in vitro. Indeed, they were inhibitors of this enzyme. Adamantanylglycine, adamantanyl-L-leucine, and adamantanyl-L-phenylalanine were also not hydrolyzed by leucine aminopeptidase.

A series of analogs of N-benzylimidazole was prepared and tested for hypolipidemic activity. Both plasma cholesterol and triglyceride-lowering activity were found in several members of the series. The most active compounds were N-3-methoxy-, N-4-methoxy-, and N-4-methylbenzylimidazole. Structure-activity relationships are discussed.

N-Heterocyclic acraldoximes methiodides, where the heterocyclic residues are 2-, 3-, and 4-pyridyl, 2-(1-methyl)imidazolyl or 4-pyrimidyl, were prepared and tested for their reactivating potency on acetylcholinesterase inhibited from diisopropylphosphorofluoridate (DFP). The in vitro testing revealed that the new compounds are good reactivators of the phosphorylated electric eel cholinesterase. The structure-activity relationships are briefly discussed.

Two series of (E)- and (Z)-N-alkyl-alpha,beta-dimethylcinnamamide derivatives were prepared and the biological activity of these compounds was investigated in a series of pharmacological tests. All compounds tested had clear activity on the CNS; generally, this was depressant with E isomers, while Z isomers always caused marked stimulation (tremors and convulsions). Some of the E isomers also had a clear-cut anticonvulsant activity as shown by the antagonistic effect on pentylenetetrazole-induced seizures in the mouse. The NMR spectra of these compounds, which confirm their configurations, are discussed.

Hydantoin derivatives of varying lipophilic character were prepared as nitrogen mustard carriers for CNS antitumor evaluation. Activity was studied in the murine ependymoblastoma brain tumor system. Multiple cures were observed for three of the four analogs examined. The compounds were also active in the intraperitoneal leukemia L1210 and P388 systems as well as in B16 melanoma and Lewis lung carcinoma.

A series of (2-pyrimidinylthiomethyl)carbonitriles and -carboxamidoximes was synthesized and the antiarrhythmic effects were evaluated against ventricular arrhythmias as measured by the electrical fibrillatory threshold in the anesthetized dog. Structure-activity studies indicated 2-[4-(p-chlorobenzylamino)-6-methyl-2-pyrimidinylthio]acetamidoxime dihydrochloride (6a) and 2-[4-(1,3-benzodioxol-5-ylmethylamino-6-propyl-2-pyrimidinylthio]acetamidoxime (6g) to be the most potent members of the series.

The 2,5-dimethyl-2'-hydroxy-9alpha- and-beta-propyl-6,7-benzomorphans were synthesized from 4-methyl-3-propylpyridine in five steps, in an overall yield of 14 and 5%, respectively. The required 4-methyl-3-propylpyridine was prepared in an overally yield of 34% by a four-step sequence. The benzomorphans were about as potent as, or more potent than, morphine in vivo.

The highest level of confidence can be placed in calculated log P values when (1) the log P of a parent solute is known, (2) pi constants for the required substituent(s) are available, and (3) the substituents either do not have an effect on groups already present in the parent or else this effect has been previously determined. In some instances there are no values available for any related structures which could serve as a parent; then, rather than substitute groups for hydrogen, it is easier to begin "from scratch", as suggested by Nys and Rekker, and assemble the structure from fragments, each of which has been assigned a hydrophobic value. In the present paper some new log P values for the lower alkanes and the inert gases are analyzed with the view of separating hydrophobic effects according to volume (including branching and flexibility) and polarity. Modified fragment values appear to enable reliable calculations to be made for a wider range of structures than was possible with the originally proposed constants.

The experimental Rm values for a series of phenols were obtained by a reversed-phase TLC system. The extrapolation from a range of linear relationship between experimental Rm values and acetone concentration provided a set of extrapolated Rm values. This were used for studying the relationship between structure and activity in vitro and in vivo. The possibility to obtain by means of the extrapolation technique the Rm values in a standard system for serveral series of chemotherapeutic agents is pointed out.

The chromatographic Rm values of three series of steroids were determined by means of a reversed-phase system. The Rm values at 45% acetone in the mobile phase were shown to be correlated with the partition coefficients in an ether-water system. However, an almost equally good correlation was found when using extrapolated Rm values. The extrapolation technique could provide a standard system. The relationship between biological data and Rm values pointed out the important role of the lipophilic character in regulating the activity of steroids. In particular, the dependence of protein binding absorption and biotransformation on lipophilic character might strongly influence the availability of steroids at the site of action.

Regression analysis of the potency of inhibition of monoamine oxidase by 47 propynylamines revealed that there are three determinants of inhibitory potency: (1) the smallest substituent on the nitrogen must be methyl or hydrogen in order for any activity to be observed; (2) potency is parabolically related to pKa-the optimum pKa is 6.2; and (3) ortho-substituted benzylamine analogs are ten times more potent than predicted on the basis of pKa values. The optimum pKa cannot be explained by differences in fraction ionized but rather in terms of the multistep sequence whereby these compounds inhibit MAO. A very slight positive effect of hydrophobicity on potency was found. The potency of several analogs not included in the original analysis was predicted.

A general synthetic route from elymoclavine (4a) to a variety of C-17 substituted 8-ergolenes has been established. [The C-17 position is the carbon attached to C-8 of the ergoline (1) skeleton as indicated in structure 2.] This route involves displacement reactions on the allylic chloride (4h) prepared from 4a by reaction with thionyl chloride. Conversion of the naturally occurring tricyclic clavines, chanoclavine I (5a) and isochanoclavine I (5b), to the tetracyclic clavine, agroclavine (4i), has been achieved. The new compounds prepared were tested for prolactin-inhibiting ability and were found to possess activity. One of the compounds prepared, 6-methyl-8-ergolenylacetamide (4k), was very potent, comparing favorably in activity to the best prolactin inhibitors reported to date.

1,3,8-Triazabicyclo[4.4.0]decan-2-ones and -thiones varying substituents at positions 3 and 8 have been synthesized. When tested in cotton rats for their antifilarial activity against Litomosoides carinii, some of the compounds showed moderate microfilaricidal activity.

A number of 2-chloromethyl and 2-bromomethyl derivatives of naphthoquinones, quinolinediones, and naphthazarins were designed and synthesized as potential bioreductive alkylating agents, and the antitumor activity of these compounds was assessed in mice bearing Sarcoma 180 ascites cells. The results indicated that, with the exception of 3-benzamido-2-chloromethyl-1,4-naphthoquinone, which was inactive, all newly synthesized naphthoquinones possessed strong antitumor activity against this neoplasm. 6,7-Bis(bromomethyl)quinoline-5,8-dione had moderate inhibitory activity against Sarcoma 180 at its optimal daily dosage level of 15 mg/kg. 3-Bromo-2-bromomethyl- and 3-bromo-2-chloromethylnaphthazarin produced a moderate extension of the life span of tumor-bearing mice; whereas, in contrast, 6,7-dimethyl analogs of these agents were inactive when employed in daily doses up to 40 mg/kg body weight.

A large number of oxanilic acid esters and N-heteroaryl oxamic acid esters were prepared and found to have antiallergic activity using the rat passive cutaneous anaphylaxis (PCA) test. Many of the oxanilic acid esters are active orally, with the most active species having an aryl 2'-carbamoyl group and a 3'-methoxy group. Hydrolysis of the ester from the oxanilic ester moiety causes a loss of oral activity.

(+/-)-5-Amino-2-hydrazino-2-methylpentanoic acid [alpha-hydrazino-alpha-methyl-(+/-)-ornithine] was obtained from 1-phthalimidopentan-4-one by treatment with hydrazine and KCN followed by acid hydrolysis. The title compound was found in vitro to be a potent competitive inhibitor of ornithine decarboxylase obtained from the prostate glands of rats. This inhibition was abolished at high concentrations of pyridoxal phosphate. The title compound also blocked the increase in putrescine levels normally observed in bovine lymphocytes transformed by conconavalin A.

To explore the effect of lipophilicity on antilipidemic activity in the Triton WR-1339 induced hyperlipidemic rat model we synthesized the 6-cyclohexyl, phenyl, and phenoxy analogs of ethyl chroman-2-carboxylate. Results obtained were analyzed in light of the biological activity observed for the 6-chloro-substituted and unsubstituted chromans, the 6-chlorochroman-4-one ester, and the 6-chloro-, phenyl-, and phenoxychromone esters. The suggestion is made that chromones likely exert their antilipidemic effects by a somewhat different set of mechanisms than do the chromans and clofibrate. Whereas the 6-chlorochromanone ester is inactive, the 6-chlorochromone ester is active in both normal and hyperlipidemic Sprague-Dawley rats. The major differential effect was observed for ethyl 6-cyclohexylchroman-2-carboxylate which did not lower cholesterol levels but returned triglyceride levels to normal in hyperlipidemic rats.

The fibrinolytic activity of nine 2-phenethynylcyclopropanecarboxylates was measured in the hanging clot test. The structure-activity relationship is given by log 1/C equals 0.54 log P + 2.01 where P is the octanol-water partition coefficient of the carboxylate ion pair and C is the molar concentration of the drug. The equation obtained for the cyclopropanecarboxylates is compared with similar equations for benzoates, salicylates, and N-phenylanthranilates.

The structure of a compound previously reported as 2,3,4,5,6,7-hexahydro-2,2-dimethyl-8-hydroxy-6-methyl-10-pentyl-3,7-methano-1-benzoxonin (1) is shown to be actually 3,4,5,6-tetrahydro-7-hydroxy-2-methyl-5-isopropyl-9-pentyl-2,6-methano-2H-1-benzoxocin (2a).

Phenacyl-riphenylphosphorane (1a) and several analogs substituted in the meta position of the phenacyl group lowered blood glucose levels in 48-hr fasted rats. The corresponding phosphonium salts had comparable hypoglycemic activity. Two compounds (1a and 1b) were also hypoglycemic in fed rats, but hypoglycemia could not be elicited in another species.

With expanding class sizes and increased proportions of women and minority group medical students, questions are frequently asked concerning recent trends in retention and graduation rates. In this article the authors report on a national Association of American Medical Colleges study of new entrants in the 1968 through 1972 first-year classes of U.S. medical schools and place this study in historical perspective. They note that recent attrition rates are only about half that of the 9 percent reported in the last national AAMC study of 1949-1958 entrants. Although the retention rate for women and for underrepresented minorities is still slightly less than that for white males, the gap appears to be narrowing. Suggestions for optimum retention include: (a) enlarging the pool of minority applicants, (b) improving the techniques of student selection, and (c) increasing the flexibility of academic programs in the medical schools.

There have been many reports stating that the traditional criteria of the Medical College Admission Test (MCAT) and undergraduate grade-point average (GPA) have little, if any, value in predicting success in the preclinical years of medical school among students from underrepresented (racial and ethnic) minority groups. In contrast to previous articles this report emphasizes that traditional criteria and the quality of the undergraduate college attended are of some statistical value in predicting success in the preclinical years of medical school among accepted students from under represented minority groups. Of these criteria, the one with the greatest predictive value is the selectivity of the undergraduate college attended.

Although there is less attrition from medical school now than in prior years, 500 or more students can be expected to withdraw from American medical schools during each academic year. Continuing study of the problem is, therefore, warranted. Personality inventory, cognitive, and application data, all gathered at the time of admission, were examined for 1,014 graduates and 57 dropouts; separate analyses were conducted for the 17 who departed for academic reasons and the 40 whose attrition was attributable to other causes. Correlational analyses were also conducted in which graduates, nonacademic dropouts, and academic dropouts were scaled in a 4-3-1 continuum. The best predictor of this graduation versus dropout hierarchy was given by a six-variable combination, including scores on the Quantitative ability subtest of the Medical College Admission Test and premedical grades for the last two terms, with positive weightings; personality inventory scales for status potential, socialization, and communality, also with positive weightings; and a personality scale for conformist achievement drive, weighted negatively.

Recent studies of the validity of student ratings of teaching leave much to be desired. Five of these studies are evaluated on the basis of adequacy of design, validity, and generalizability; and one of the studies is used as a model for further inquiry in this area. It is then argued that student evaluations of teaching can provide useful information relevant to the improvement of instruction. However, in order to use such evaluations, improved methods of data collection and analysis are needed. A primary improvement would be in the area of generalizability. A plan for expanding the use of student evaluations from personal utility to general applicability is outlined.

Effects of changes in a pediatric practice--expansion of the number of pediatricians and incorporation into a university hospital setting--on continuity of care and utilization were examined by means of a longitudinal study of a sample of 63 families. Continuity of care was measured by the following index: the number of visits with own physician divided by the total number of pediatric visits per year. Although continuity of well-child visits remained unchanged at the university setting, the continuity of sick visits declined markedly. An increased use of doctor visits for illness care was observed; its relationship with the decline in continuity is analyzed and discussed. While continuity is inherent in a small partnership practice, it is not so in a larger medical organization, particularly when involvement in patient care is part time. In such an organization, deliberate arrangements that enable patients with acute needs to receive care from their own doctors are needed.

Summary statistics of various hematologic and serum biochemical measures are presented for a colony of 74 chimpanzees (Pan troglodytes). Covariance analysis of longitudinal values revealed a progression of some measures with maturity. Equations for evaluating these measures as they relate to the health of individual colony members and new additions to the colony were formulated. From these equations, confidence bounds (95%), which can be regarded as normative ranges, were established for each of the measures. The literature on hematologic and serum biochemical values in the chimpanzee, especially as they pertain to the evaluation and progression of values, is reviewed.

Rates of change of cell volume were measured in suspensions of the halophilic green algae Dunaliella parva subjected to changes in cation composition and concentration of the outside medium. Measurements were made with a particle size analyzer and results were checked by direct microphotography. For any one salt solution, changes in cell volume with concentration were consistent with the Boyle-Van't Hoff model of an osmometer. Nonosmotic volume comprised 60-80% of total cell volume and was sensitive to the nature of the cation, increasing in the order Cs less than K less than Na less than Ca less than Mg. Kinetics of volume change in response to changes in outside salt concentration are best described by two kinetic coefficients differing by one order of magnitude and dependent on the nature of the outside cation (decreasing in order Cs greater than K greater than Na greater than Mg) as well as on direction of water flow.

The effect of different extracellular alkaline-earth cations (Ca2+, Mg2+, Sr2+, Ba2+) upon the threshold membrane potential for spike initiation in crayfish axon has been studied by means of intracellular microelectrodes. This was done at the following extracellular concentrations of the divalent uranyl ion (UO2/2+): 1.0 X 10(-6) M, 3.0 X 10(-6) M, and 9.0 X 10(-6) M. At each concentration employed, extensive neutralization of axonal surface charges by UO2/2+ was evidenced by the fact that equal concentrations (50 mM) of alkaline-earth cations did not have the same effect on the threshold potential. The selectivity sequences observed at the different uranyl-ion concentrations were: 1.0 X 10(-6) M UO2/2+, Ca2+ greater than Mg2+ greater than Sr2+ greater than Ba2+; 3.0 X 10(-6) M UO2/2+, Ca2+ greater than Mg2+ greater than Ba2+ larger than or equal to Sr2+; 9.0 X 10(-6) M UO2/2+, Ca2+ approximately Ba2+ greater than Sr2+ greater than Mg2+. These selectivity sequences are in accord with the equilibrium selectivity theory for alkaline-earth cations. At each of the concentrations used, uranyl ion did not have any detectable effect on the actual shape of the action potential itself. It is concluded that many (if not most) of the surface acidic groups in the region of the sodium gates represent phosphate groups of membrane phospholipids, but that the m gates themselves are probably protein-aceous in structure.

Unidirectional ion fluxes are measured in cells isolated by a trypsination-dissection method from the epithelium of the frog Leptodactylus ocellatus. Potassium seems to be contained in a single cellular compartment. The influx of potassium is 0.0068 mumole min-1 mg-1 of dry weight and is carried by a ouabain-sensitive pump. Sodium seems to be contained in two cellular compartments, one of which does not exchange its Na within the experimental period. The possibility that these compartments reflect the existence of different types of cells is not discarded. 49% of the rate constant for the Na efflux is ouabain-sensitive and 23% is ethacrynic-sensitive. Under control conditions the permeability to potassium (PK), sodium (PNa) and chloride (PC1) are 7.6 X 10(-5), 2.6 X 10(-5) and 2.8 X 10(-5) liters/min mg, respectively. The value of PNa is much higher than predicted by current electrical models of the epithelium. The discrepancy might offer some insight into the nature of the "inner facing barrier" of the skin.

The influx and efflux of calcium (as 45Ca) and influx of sodium (as 24Na) were studied in internally dialyzed squid giant axons. The axons were poisoned with cyanide and ATP was omitted from the dialysis fluid. The internal ionized Ca2+ concentration ([Ca2+]i) was controlled with Ca-EGTA buffers. With [Ca2+]i greater than 0.5 muM, 45Ca efflux was largely dependent upon external Na and Ca. The Nao-dependent Ca efflux into Ca-free media appeared to saturate as [Ca2+]i was increased to 160 muM; the half-saturation concentration was about 8 muM Ca2+. In two experiments 24Na influx was measured; when [Ca2+]i was decreased from 160 muM to less than 0.5 muM, Na influx declined by about 5 pmoles/cm2 sec. The Nao-dependent Ca efflux averaged 1.6 pmoles/cm2 sec in axons with a [Ca2+]i of 160 muM, and was negligible in axons with a [Ca2+]i of less than 0.5 muM. Taken together, the Na influx and Ca efflux data may indicate that the fluxes are coupled with a stoichiometry of about 3 Na+-to-1 Ca2+. Ca efflux into Na-free media required the presence of both Ca and an alkali metal ion (but not Cs) in the external medium. Ca influx from Li-containing media was greatly reduced when [Ca2+]i was decreased from 160 to 0.23 muM, or when external Li was replaced by choline. These data provide evidence for a Ca-Ca exchange mechanism which is activated by certain alkali metal ions. The observations are consistent with a mobile carrier mechanism which can exchange Ca2+ ions from the axoplasm for either 3 Na+ ions, or one Ca2+ and an alkali metal ion (but not Cs) from the external medium. This mechanism may utilize energy from the Na electrochemical gradient to help extrude Ca against an electrochemical gradient.

It has been reported earlier that when rat liver is dispersed to a single cell suspension, the parenchymal cells lose the ability to take up pyrimidine bases but acquire the ability to take up RNAase and macromolecular nucleic acids. It is now shown that these changes are largely reversed on intraperitoneal reaggregation of the parenchymal cells and that, in these respects, the aggregates behave more like the organized tissue than like the dispersed cells.

The accumulation of several amino acids in the acid-soluble fraction and their incorporation into protein in rat liver parenchymal cell suspensions, has been shown to depend on the concentration of cells in the incubation medium; the uptake, both in the acid-soluble and the acid-insoluble fractions, decreased as the cell concentration increased from 0.03 X 10(6) cells/ml upwards, reaching a plateau at high cell concentrations (3-5 X 10(6) cells/ml). The uptake values at high cell concentrations were the same as those obtained in liver slices in which a similar effect was not observed. Evidence is presented which suggests that this phenomenon is mediated by a material released from the cells in suspension, which is inhibitory to enhancement of the uptake of amino acids by these cells over and above the value obtained in normal, adult liver slices.

The abdominal escutcheon, and certain aspects of pre-anal organ morphology, have been studied in Sphaerodactylus spp. and Gekko vittatus respectively. These epidermal modifications are male characteristics. The sphaerodactyline escutcheon becomes larger by the peripheral addition of specialized scales with increasing size of the individuals: this relationship is much more clearcut in S. cinereus than in the notatus species group (sensu Shreves, '68), and the possible reasons for this are discussed. The number of pre-anal organs varies between populations of G. vittatus, but within populations remains constant throughout life. Individual organs increase steadily in size throughout life. These data are discussed with reference to current interpretations of gekkonid gland evolution, and of factors controlling epidermal cell proliferation and differentiation.

In Tilapia mossambica organized lymphoid tissues are present in the thymus, head-kidney and spleen, whereas they are lacking in pericardial tissue, liver, mesonephros, intestine and rectum. No lymphoid tissue was observed in the chondrocranium and cartilaginous viscerocranium of young adults. The thymus in Tilapia is encapsulated by thin strands of collagen fibers and consists of outer, middle and inner zones. While middle and inner zones are comparable to the thymic cortex and medulla of higher vertebrates, the homology of the outer zone is not clear. At the anterior end of the thymus, a loose aggregation of lymphocytes without a definite boundary has been observed. The head-kidney is characterized by the presence of lymphoid follicles, a subcapsular sinus, a hilus-like area and lymphatic vessels. The spleen is grossly divisible into white pulp and red pulp; the white pulp contains only a reticular area without definite lymphoid centers and the latter contains predominantly erythrocytes. Morphological changes in the lymphoid organs associated with immune response have been discussed.

The gross and microscopic anatomy of epidermal glands has been studied in laboratory maintained tokays (Gekko gecko), and house geckos (Hemidactylus bowringii) captured from the wild throughout the year. Annual testicular activity in the house gecko has also been studied. While no significant differences in glandular development at various times have been observed in G. gecko, there are clear-cut annual cycles in H. bowringii. The evolution of epidermal glands in gekkonid lizards is reviewed; the cellular dynamics of beta-glands are compared with those of unspecialized epidermis; the possibility that gekkonine epidermal glands respond to quantitative variation in circulating testosterone titers is discussed.

Cell suspensions obtained by the dissociation of unincubated chick embryo blastoderms were allowed to reaggregate on a gyratory shaker for 24-48 hours. The reaggregates which form during this period consist of an inner phase of tightly packed cohesive cells surrounded by an external phase of loosely packed cells. This sorted out arrangement achieves its definitive form between 24 and 48 hours of rotation culture. It was determined that the external phase consists of primitive ectoderm and that the internal phase consists of primitive endoderm. Both 24- and 48-hour reaggregates were examined in the electron microscope and observations were directed to areas of close membrane apposition between cells. In 48-hour reaggregates, primitive endoderm cells were joined by many specialized junctions (desmosomes). The formation of desmosomes in reaggregates of dissociated unincubated chick embryo cells was correlated with the sorting out process.

A consideration of head development in two species of Esox, lucius and americanus (ssp. vermiculatus) representing the two subgenera Esox and Kenozoa respectively, focused on the significance of the variations of the latero-sensory canal system, its associated bones, and other skeletal elements. In living forms only aspects of "regression" or specialization can be studied. Canals tend to be reduced to pit lines first at their termini but can be broken in their course. Pit lines range from nearly canals to surface structures, or even fail to develop. The number of neuromasts varies. Canal bones develop from two centers: neuromast related and deeper membranous centers which may have no relationship to neuromasts. Tooth-bearing and non-canal-related dermal bones have only membranous (original) centers. The number of neuromasts associated with a bone usually does not affect its development or form. In the case of the circumorbital bones, the extrascapulars, and the nasal, a one to one relationship has developed by regression--towards the development of the latero-sensory component only. The idea that reductions in bone number are commonly traceable to fusion is rejected although examples of fusion are know. Most bones that disappear are simply lost (no blastema or other evidence of their presence seen in development). The relationship between dermal bone and chondral bone is examined and there is evidence of the former giving rise to the latter. The ontogenic order of appearances shows a feeding (functional) correlation.

The nucleus rotundus of 21 species of teleosts was studied by a modified Bodian and the Golgi method to clarify the histological organization, with special reference to the cell lamination and the glomerular formation. The common components of the nucleus in all species are as follows: a thick fiber bundle which comes from the commissura horizontalis and enters the nucleus from the dorsal surface, many small cells, large cells, glomeruli, and a surrounding fibrous capsule. The nuclei of all species studied are classified into three types mainly on the distribution of the small cells, and to a lesser degree on the location of the large cells and the glomeruli. The first type of nucleus has small cells, large cells and glomeruli throughout its extent. In the second type of nucleus, many small cells form a peripheral cell layer, while the large cells and glomeruli are found all over the nucleus. The third type of nucleus is clearly laminated. It is composed of four layers arranged concentrically around a central fiber net in the following order: a glomerular layer, a fibrous layer, a small-cell layer, and a peripheral fibrous capsule. In some species, the large cells are located in the fibrous capsule, and all glomeruli contain a star-like structure, which corresponds to the tips of the large cell dendrites.

In vivo and in vitro experiments on the endocrine relationships of epidermal glands in the tokay Gekko gecko, and the common house gecko Hemidactylus bowringii are reported. The results show that certain aspects of beta-gland differentiation involve a synergistic action between androgens and those hormones responsible for controlling the normal shedding cycle, while other aspects are solely under androgenic control. Pre-anal organ activity appears to be solely under androgenic control.

1. Parvalbumins were isolated from the white muscle of Cynoscion regalis, Leiostomus xanthurus, and Menticirrhus americanus of the Sciaenidae and Pomatomus saltatrix of the Pomatomidae. 2. Menticirrhus contains three isoparvalbumins. The other species contain two isoparvalbumins which are designated "fast" and "slow" in accord with their electrophoretic mobilities. Measurements of the denatured molecular weights show the "slow" isoparvalbumins have slightly larger apparent molecular weights, but all apparent molecular weights are in the range 10,400-14,000. 3. Amino acid compositional studies indicate that the fast and slow isoparvalbumins in these fish represent two distinct evolutionary lineages which appear to be evolving at different rates.

We have prepared a variety of derivatives of adenosine which, at neutral pH's, carry protonated amine functions. These derivatives form stable helical structures with polyuridylic acid, but the melting points are not substantially higher than those of helical complexes formed by adenosine derivatives lacking cationic groups.

Structural transitions in oligomeric proteins due to ligand binding are important in biomolecular regulatory processes. The transitions may occur on the secondary, tertiary or quarternary structure levels. Detailed consideration of the time sequence of ligand binding to the oligomer shows that there is an intrinsic dynamic asymmetry in all oligomer transitions, even if the initial and the final state are completely symmetric. This asymmetry has important bearing on the evolution and the divergence of the primary structure (amino acid sequence) of oligomeric proteins. It may explain (at least in part) the occurrence of oligomeric proteins with similar but not identical protomers. Certain specific groups of oligomers are shown to be under greater evolutionary pressure for protomer structure divergence. The dynamic asymmetry of oligomer transitions also results in higher complexity in reaction kinetics. Some implications on ribosome structural evolution are discussed.

The local stability of unbranched biosynthetic pathways is examined by mathematical analysis and computer simulation using a novel nonlinear formalism that appears to accurately describe biochemical systems. Four factors affecting the stability are examined: strength of feedback inhibition, equalization of the values among the corresponding kinetic parameters for the reactions of the pathway, pathway length, and alternative patterns of feedback interactions. The strength of inhibition and the pattern of feedback interactions are important determinants of steady-state behavior. The simple pattern of end-product inhibition in unbranched pathways may have evolved because it optimizes the steady-state behavior and is temporally most responsive to change. Stability in these simple systems is achieved by shortening pathway length either physically or, in the case of necessarily long pathways, kinetically by a wide devergence in the values of the corresponding kinetic parameters for the reactions of the pathway. These conclusions are discussed in the light of available experimental evidence.

The major photoproduct obtained on irradiation of gaseous NH3 and CO mixtures is ammonium cyanate; lesser amounts of urea, biurea, biuret semi-carbazide, formamide and cyanide were observed. The formation of the major gas phase photolysis product may be rationalized by the following reaction sequence: (see article). Urea is probably formed from NH4NCO in a thermal reaction while formamide may result from the disproportionation of NH2CO. Photocatalytic syntheses of 14C-urea, -formamide, and -formadehyde are effected by irradiation of 14CO and NH3 in the presence of Vycor, silica gel, or volcanic ash shale surfaces. These syntheses are catalyzed by ultraviolet wavelengths longer than those absorbed by the gaseous reactants. The syntheses are also effected when the surface material is first irradiated in the presence of CO followed by a dark incubation with NH3. Apparently, the initiating step is a light dependent formation of a reactive form of CO on the surface. A discussion is given on the possible contribution of these reactions to the abiotic synthesis of organic nitrogen compounds on Mars, on the primitive Earth and in interstellar space.

The formation of packets of parallel oriented platelets and separating distances of several angstrom units in montmorillonite-water systems produces an intrinsic inhomogeneity with respect to the proton donating power of internal and external zones. Stable packets can be induced by both inorganic and organic molecules or ions, in suspensions or in drying-out systems. The coexistence of zones with different proton donating power was demonstrated by the pH-sensitive color reaction of benzidine, where stable packets of montmorillonite platelets were formed by the use of either paraquat or diquat. The close proximity of the two types of zones, which can be of the order of several angstroms, produces the conditions which were defined by Katchalsky as essential for the polymerization of amino acids. Since these enviromental conditions are quite common in nature, both at present and in prebiotic times, it is proposed that the inhomogeneity of clay-water systems with respect to proton donating power should be taken into account in both theoretical and experimental efforts to demonstrate the catalytic activity of clays in prebiotic synthesis.

The notion of the probability of back mutation is introduced and the method of probability generating functions is used in order to simplify and unify the Holmquist's (1972) investigation of the effect of multiple hits on nucleotide differences between homologous DNAs. We obtain explicit expressions for the distribution of the number of hit nucleotide sites, the number of altered sites, and the number of differences between two homologous DNAs, as functions of the total number of hits. For the case where the hit rate is a known function of time, we derive a formula for extending these results as functions of time.

Exposure of mouse and rat tumors of various types to more than 600 nm light 24 or 48 hours after an injection of hematoporphyrin resulted in a substantial number of long-term cures. Since hematoporphyrin is preferentially retained in tumor tissue, selective tumor destruction could be obtained. Light penetration studies and the high efficiency of this technique indicated its applicability even to certain deep-seated human tumors.

Quinoxaline 1,4-dioxide was fed to 400 rats at levels of 10 mg or 1 mg/kg body weight for 18 months. It produced a high incidence of nasal and liver tumors only in the group fed 10 mg/kg. Of diverse histologies, the nasal tumors included anaplastic carcinomas, adenocarcinomas, squamous cell carcinomas, neuroepitheliomas, basal cell carcinomas, and a single fibrosarcoma. The nasal epithelium not involved in the neoplastic process showed dysplasia and hyperplasia.

Sequential evaluations were made of the morphology and biochemistry of trigeminal nerves from control and ethylnitrosourea (ENU)-exposed rats from 1 day to 6 months of age. Distinct increases in cellularity were evident as early as 20 days after exposure to ENU. Corresponding increases in N-acetyl-beta-glucosaminidase and beta-glucuronidase were detected at the same time. Transplantation studies were performed with grossly normal trigeminal nerves from 32-, 63-, and 91-day-old control and ENU-exposed rats. One of eight nerves from the 32-day-old ENU-exposed donors developed into neurinomas at the site of transplantation. No tumors developed from nerves of controls. These results indicate that the early increases in cellularity and acid hydrolase activities represent neoplastic rather than preneoplastic changes.

A case-control dietary study of 198 patients with cancer of the colon and two matched control groups demonstrated a significantly lower fiber consumption frequency among the cancer patients. This difference was not confined to a few items. Of the 73 items on the fiber list, 61 were eaten less often by the cancer patient than by a neighborhood control, and 57 were consumed less frequently than by a surgical control. These findings support the hypothesis that low-residue foods play an etiologic role in colon carcinogenesis. A mechanism related to the possible potential carcinogenic properties of degraded biliary compounds may be implicated.

The carcinogenic and cocarcinogenic activity of synthetic smog, ferric oxide (Fe2O3) dust, and a mixture of the two air contaminants was determined in a long-term inhalation study with Syrian hamsters. Inhaled Fe2O3 particles definitely enhanced diethylnitrosamine tumorigenicity in the peripheral lung. Synthetic smog did not. When tested at a concentration of 40 ppm methane equivalents or 40 mg/m3, respectively, neither air pollutant by itself appeared carcinogenic. Fe2O3 caused pulmonary fibrosis and synthetic smog caused alveolar bronchiolization in many of the exposed animals.

The effects of topical administration of 3-methylcholanthrene (MCA) or its metabolites on BALB/cKi mice were reported on inflammatory skin reactions, the alterations in epidermal thickness, the number of nucleated cells, pyknotic nuclei and/or nuclear fragments, and mitotic figures in the interfollicular epidermis (IFE). In the two-stage carcinogenesis system, MCA, the powerful complete carcinogen, induced an ordered sequence of cell changes strikingly similar to those caused by tumor-promoting agents such as the phorbol esters. These changes were absent after application of the "K-region" oxide of MCA. Other MCA metabolites also failed to induce notable inflammation, epidermal hyperplasia, and/or hypertrophy. Several MCA derivatives, however, caused a thinning of IFE paralleled by an increase in the relative number of pyknotic nuclei and a decrease in the total number of epithelial cells. The inhibitor of polycyclic hydrocarbon metabolism alpha-naphthoflavone did not prevent MCA-mediated skin reactions but, under suitable conditions, apparently potentiated the hyperplastic effects of MCA. The findings indicate that important events in the promotion phase of MCA-mediated skin carcinogenesis might be associated with the parent compound rather than with one of its metabolites.

Spontaneous adenocarcinomas of the ventral prostate were present in 7 of 41 aged (34- to 37-month-old), virgin, untreated male A X C rats. The only consistent gross evidence of possible neoplastic involvement was intraprostate hemorrhage. The principally intraglandular neoplasms were composed of markedly anaplastic epithelial cells which retained a moderate propensity to form glandular patterns. The nuclei of the neoplastic cells were pleomorphic, vesiculated, enlarged, and hyperchromatic. Mitotic figures were frequent. Interglandular connective tissue was invaded in one rat; however, metastases were not demonstrated.

Tumors were induced sc in (BALB/c x DBA/2)F1 female mice by various concentrations of 3-methylcholanthrene (MCA) in paraffin pellets. There was an inverse relationship between MCA concentration and tumor latency (interval between MCA implantation and detection of gross tumor). The tumors were transplanted into syngeneic recipients, and material from this first transplant generation was used to immunize a series of syngeneic mice; any resulting growth was excised. Nonimmunized mice were controls. Immunized and control mice were irradiated and given an sc inoculation of a near-threshold number of tumor cells. Tumor growth from that inoculation was measured weekly in both groups and the antigenicity ratio (mean tumor size in controls/mean tumor size in immunized mice) was calculated. In a series of tumors with similar latencies, the only ones with high antigenicity ratios were those resulting from the high MCA concentration. The results suggested that tumors induced by low levels of oncogen may be good models of spontaneous neoplasia, strengthened the hypothesis that "spontaneous' tumors may actually result from low levels of oncogen, and indicated that neoplastic transformation and the development of immunogenicity are, at least in chemically induced tumors, independent changes that may be produced in the same cell when the concentration of oncogen is sufficient.

After one dose of adriamycin, a subacute cardiomyopathy was observed in the mouse by both light and electron microscopy. The microscopic alterations were characterized by single-cell necrosis and mitochondrial degeneration. These lesions were similar to those seen in man and shortly preceded fatal toxicity.

A cage for continuous intra-arterial or intravenous infusion is described. Major features are: a) The animal is free to move during infusion, b) loss of the infused solution is avoided, c) cleaning and decontamination are simple, and d) infusion can continue for weeks.

Highly immunogenic sublines of L1210 and LSTRA lymphomas were obtained from athymic (nude) mice treated with 4(5)-(3,3-dimethyl-1-triazeno)imidazole-5(4)carboxamide (DIC) in vivo. Conventional mice, compatible with the parent tumor, rejected the DIC-treated sublines and were relatively resistant to a subsequent challenge with the parent lines. The DIC-treated sublines were not rejected by athymic mice, which indicated that the transplantation resistance to these tumors in conventional mice was thymus-cell dependent. In addition, there was marginal or no increase of tumor-cell immunogenicity when the parent lines were passaged in nude mice without DIC treatment. This indicated that the DIC-dependent immunogenic changes in DIC-treated leukemic conventional mice could not be ascribed merely to protection by naturally occurring antigenic clones that resulted from DIC-induced immunodepression.

Groups of AKR mice bearing spontaneous leukemia-lymphoma were treated with five different combinations of chemotherapy or chemoradiotherapy. Each treatment combination was given in two sequences--high dose first and low dose last, or low dose first and high dose last--administered over 6-7 days. When the initial treatment was a high dose of chemotherapy, radiotherapy, or chemoradiotherapy, mortality in the first 24 hours exceeded 40%, and at least 70% of the mice in each group were dead within 2 weeks. When low-dose chemotherapy was given first, mortality in the first 24 hours was minimal but, most significantly, no deaths occurred in the 24 hours after subsequent high-dose treatment. In the most successful group (100 mg cyclophosphamide/kg on day 0, and 250 mg cyclophosphamide/kg and 400 R total-body X-irradiation on day 7), the median survival time increased significantly as compared with the median survival time among mice given the same regimen in reverse sequence (p less than 0.001) or among untreated control mice (p less than 0.01). With this regimen, survival 60 days after the last treatment was 47%. No mouse survived 30 days when the sequence of treatments was reversed. From these results, we conclude that chemotherapeutic and chemoradiotherapeutic regimens for AKR spontaneous leukemia-lymphoma should be designed so that low, minimally lethal doses precede higher doses.

Samples of tumor and normal mucosa from 32 patients with adenocarcinoma of the colorectum were examined for their capacity to bind radioiodinated antibody to carcinoembryonic antigen (anti-CEA) lgG. Twenty-three (72%) of the tumors bound significantly more antibody than the respective normal mucosa. The results indicate that radiolabeled anti-CEA may be useful in the in vivo localization of CEA-producing tumors and metastases in man, and may have application in vitro as a diagnostic marker of precancerous change in colorectal biopsies from patients at risk of developing colorectal cancer.

Bone marrow cells from BALB/c mice infected with Rauscher erythroblastosis virus produced five to twenty-five times more erythroid colonies in vitro in the absence of erythropoietin (EP) as compared to normal cells. A good correlation existed between the state of the disease and the number of hormone-independent erythroid colony-forming cells (CFU-E). A significant number of hormone-independent CFU-E was found as early as 3 days after infection. A linear relationship existed between the number of cells plated and the number of erythroid colonies formed in vitro. Addition of EP did not enhance colony formation, even at low cell concentrations. Feeder layer experiments demonstrated that EP-independent colony formation was not due to the production of endogenous EP. Repeated injections of phenylhydrazine into normal mice did not lead to the loss of EP responsiveness in vitro; this indicated that the hormone independency induced by the virus was not due to continuous erythropoietic stimulation in vivo. Besides hormone independency, the CFU-E from infected mice required less serum in the culture medium. Normal erythroid colonies regressed after 4 days of culture, but EP-independent colonies from infected mice persisted for more than 2 weeks. These three phenomena may be regarded as indicative for a physiologic transformation.